Multiple myeloma (MM) is a plasma cell (PC) neoplasm that accounts for more than 20,000 new cases every year in the United States [1-3]. Development of novel therapeutic options, such as proteasome inhibitors (PI) and immunomodulatory agents (IMiDs), has improved treatment outcomes. Patients eligible for bone marrow transplantation show 5 year survival in more than 70% of the cases, which is reduced to ˜50% in the transplant ineligible patients [4, 5]. However, the overall survival of patients carrying high-risk MM cytogenetic abnormalities is still very poor and the patients inevitably relapse [3]. Alternative novel treatment strategies are, urgently needed [6-9]. Epigenetic modifications such as DNA methylation and histone acetylation, as well as microRNA deregulation, play important roles in the pathogenesis and treatment responses of MM [10-13].
Histone acetyltransferases and histone deacetylases (HDACs) affect a broad-array of genes involved in cell cycle, apoptosis, and protein folding [14]. The first FDA-approved deacetylase inhibitor (HDACi), suberoylanilide hydroxamic acid (SAHA, vorinostat), was shown to be effective in vitro and to have clinical efficacy in T-cell lymphomas [15]. However, in MM, SAHA showed only minimal activity as a single agent [16]. For most HDACi's, the mechanism of action with respect to MM is unknown. However, at biologically achievable concentrations, it has been theorized that HDACi's can sensitize MM cells to other drugs by interfering with cell adhesion mediated drug resistance (CAM-DR) [17-19]. In two phase 1 trials, some patients with MM were effectively treated by a combination of HDACi's (SAHA, or panobinostat) with the proteasome inhibitor, bortezomib [20, 21]. However, phase 1/2 studies of combination of SAHA, or panobinostat with the immunomodulatory agent lenalidomide showed unacceptable tolerability and limited activity in lenalidomide-refractory patients [22, 23].
Recently, an orally bioavailable class I/II, phenylbutyrate-based HDAC inhibitor, AR-42 (ARNO Therapeutics, Flemington, N.J.) has been developed. AR-42 has greater anti-proliferative effects as compared to SAHA, in vitro and in vivo [24]. AR-42 also inhibits activation of STAT3, even in the presence of interleukin (IL)-6 activation signal, inducing apoptosis of MM cells [25].
Acetylation of core histones plays an important role in the regulation of gene transcription by controlling nucleosomal packaging of DNA. Deacetylation of histones results in tight packing of nucleosomes and transcriptional repression due to limited access of transcription factors to DNA targets. Histone acetylation relaxes nucleosome structures, providing greater access for transcription factors. The balance between histone deacetylation and acetylation is modulated by the histone deacetyl-transferases (HDACs) and histone acetyl-transferases (HAT). An abnormal balance of these factors is correlated with abnormal cell growth and several forms of cancer as discussed in U.S. Pat. No. 8,318,808, incorporated by reference herein in its entirety. HDAC inhibitors, in particular, change the balance between acetylation and deacetylation resulting in growth arrest, differentiation, and apoptosis in many tumor cell types. See, e.g., U.S. Pat. No. 8,318,808.
18 HDACs have been identified in humans and are characterized as being zinc dependent or nicotinamide adenine dinucleotide (NAD) dependent (Discov Med 10(54):462-470, November 2010) and are associated with the following classes: class I (HDACs 1, 2, 3, and 8); class II (HDACs 4, 5, 6, 7, 9, and 10; class III (sirtuins 1-7 (SIRT)); and class IV (HDAC 11). Id.
AR-42 is a broad-spectrum deacetylase inhibitor of both histone and non-histone proteins with demonstrated greater potency and activity in solid tumors and hematological malignancies when compared to vorinostat (i.e., SAHA). See, e.g., Lu Y S, et al., Efficacy of a novel histone deacetylase inhibitor in murine models of hepatocellular carcinoma, Hepatology. 2007 October; 46(4):1119-30; Kulp S K, et al., Antitumor effects of a novel phenylbutyrate-based histone deacetylase inhibitor, (S)-HDAC-42, in prostate cancer, Clin Cancer Res. 2006 Sep. 1; 12(17):5199-206.
Dexamethasone and lenalidomide resistance in MM has been attributed to upregulation of CD44 [26], a cell surface glycoprotein involved in cell adhesion, migration and cell-cell interactions [27]. CD44 functions as a receptor for hyaluronic acid (HA), which itself is considered a tumor marker in cancer [28, 29]. Moreover, CD44 forms a complex with STAT3 and p300 (acetyltransferase), causing STAT3 activation in a cytokine- and growth factor-independent manner [30]. Thus, pharmacological targeting of CD44 may affect different pathways in MM malignancies and be beneficial for patients with MM who are resistant to dexamethasone- and lenalidomide treatment.